Disorders of Coagulation and Hemostasis

Jeffrey T. Reisert, DOUniversity of New EnglandPhysician Assistant Program25 FEB 2010

Contact Information

Jeffrey T. Reisert, DOTenney Mountain Internal Medicine, PLLC

16 Hospital Rd.Plymouth, NH 03264

603-536-6355603-536-6356 (fax)

Jeffrey.T.Reisert@Hitchcock.org

Objectives

Understand major features of normal coagulation cascade

Know effect on coagulation by common drugs

Recognize common disorders affecting platelet and factor hemostasis

Case study

A patient, 35 years old female presents to the ED

Cc: Swollen Left leg

Case study work-up

What are physical exam findings? What else do you want to know? What is considered a thorough work-up? What is the treatment, if any?

Agenda

Normal vascular, fibrinogen, and platelet coagulation

Aspirin, heparin, and warfarin Disorders of hemostasis--->Bleeding Hypercoagulability-Excessive clotting

Phases of clotting-Delicate balance Vascular phase Platelet adhesion/aggregation/ retraction

– White thrombus Coagulation phase

– Intrinsic pathway– Extrinsic pathway– Common pathway

Remodeling

Physical exam

Bleeding Purpura-Big bruise Petechiae (Platelet diseases)

– Punctate, little bruise

Lab testing

Platelets Screening tests

– Platelet count, PT, PTT Specific tests

– Thrombin, etc. Factor assays

Tests of Platelets

Platelet count– Off CBC or separately

Platelet volume Bleeding time (BT)

– Tests vascular and platelet phase of clotting– Abnormal if low platelets, vWD, DIC, Liver

disease Platelet aggregation

Other tests

PT (Prothrombin time) PT-INR (Standardizes between labs) PTT (Partial thromboplastin time) Fibrinogen Thrombin time

Prothrombin Time (PT)

Use: Monitor warfarin, test liver function, vitamin K deficiency

Tests Extrinsic pathway– VII (first to drop), X, V, II (thrombin), I

(fibrinogen) PT prolonged with nl PTT-Usually liver

disease (or on warfarin)

PT-INR

International Normalized Ratio Standardizes the PT across different labs (Patient’s PT/Normal PT) I

Where I is a fudge factor (close to 1.0) that is different at each lab depending on which method is used to measure

This has become the standard for interpreting the protime

Warfarin (Coumadin®, Jantoven®)

Decreases synthesis of Vitamin K dependent factors

INR

D con

http://www.d-conproducts.com/

PT-INR

Normally 1 When treating with warfarin

– Goal 2-3 if atrial fibrillation, stroke, etc.– Goal of 2.5-3.5 if artificial (mechanical) valve

Partial thromboplastin time (PTT) Use: Monitor continuous IV heparin Need full tube Tests intrinsic and common pathways

– XII, XI, IX, VIII, X, V, II, I– Doesn’t measure Factor VII

IF PTT prolonged and PT normal problem is intrinsic pathway

Heparin Inhibit factor activation Given as continuous IV or sc injection ADR:

– Thrombocytopenia (Antiplatelet Ab produced)– Heparin induced thrombocytopenia (HIT)

Paradoxical thrombocytosis Like an allergic reaction Lose fingers Can die

Requires monitoring both PTT and platelets and bleeding

Low Molecular Weight Heparin Enoxaparin (Lovenox®), Dalteparin (Fragmin®) others Have found new utility in preventing abnormal clotting

– Post operative DVT prophylaxis– Post MI– Atrial fibrillation– Other uses

Easy to administer-sc Effect can’t be measured with PTT/Effect need not be

measured! Weight adjusted dosing

Factor Xa Inhibitors

Synthetic inhibitors of Factor X activation– Binds antithrombin III which inhibits formation

of Xa– Thus decreases thrombin III formation

Fondaparinux (Arixtra®)– Use for DVT prophylaxis– Not a heparin (advantage if HIT)

Fibrinogen (Factor I)

Decreased– Acquired

DIC (Most common, as this uses up fibrinogen) Liver disease (Dysfibrinogenemia) Bleed

– Congenital Elevated

– Pregnancy, oral contraceptive pills, Acute inflammation, Malignancy

Thrombin time

Mix patient plasma with commercially supplied thrombin and measure time to clot– Fibrinogen is converted to fibrin– Estimates the rate of formation of fibrin

Measures if enough fibrinogen in plasma

Thrombin time-cont

Tests last stage of coagulation Test for presence of heparin Also tests for fibrinolysis

– Presence of fibrin split products prevent fibrin monomer polymerization

– In case of clot breakdown, thrombin time prolongs

Factor assays

Exist for all factors except XIII Measured as % of normal activity VIII IX

Platelet disorders-Overview

Quantitative disorders (Low number) Qualitative disorders (Ineffective function)

Platelet count

Normal 150,000-450,000 Risk for bleeding if less than 50,000 Danger zone less than 10,000

– Risk for spontaneous cerebral hemorrhage

Platelet disorders-Quantitative

Autoimmune, Lupus Drugs

– Heparin, Quinidine, sulfa, others Infection (HIV, Mono) CLL, Sarcoidosis Thrombocytopenic purpuras

Thrombocytopenic purpuras

Low platelets with big bruises Immune thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura

(TTP)

Idiopathic thrombocytopenic purpuras (ITP) Immune reaction often

– Post infection– HIV– Lupus

Children common (viral origin) Adults may be chronic (especially young

women) Malignancies may cause, and must be excluded

ITP-Treatment

Glucocorticoids IV immunoglobulin Splenectomy

– Don’t forget pneumovax! Chemotherapy

Thrombotic thrombocytopenic purpuras (TTP) Due to unknown mechanism, develop platelet

aggregation in microcirculation What results is a form of intravascular hemolysis

with a consumptive thrombocytopenia– Increased LDH and Indirect bilirubin

Thrombocytopenia Purpura Fever

TTP-II

Resultant renal and neurological sequelae due to hypoxia

Etiology unknown May respond to plasmapheresis, steroids Hemolytic uremic syndrome (TTP with

manifestations limited to the kidney)

Platelet disorders-Qualitative Platelet. dysfunction ASA/NSAIDS/Hespan/Others Renal failure/Uremia Dysproteinemias Myeloproliferative syndromes Cirrhosis DIC

Aspirin affect on clotting

Inactivate cyclooxygenase Platelets can’t produce thromboxane A2 Lifelong for each platelet Doesn’t stop surgery!

Non Platelet disorders

Congenital Acquired

Non Platelet disorders-Congenital Hemophilias

– Gene for Factor VIII and IX lie on X chromosome

– When mutation present, X linked recessive trait– May also be due to spontaneous mutation– Two majors (A and B)

Hemophilia

Hemophilia A-Deficiency of VIII (“Classic hemophilia”)– 1:5000 live births

Hemophilia B-Deficiency of IX (Christmas disease)– 1:30,000 live births

Hemophilias-Grading

Based on amount of factor present Mild

– Bleed with surgery/trauma perhaps– Mucosal bleeding

Moderate or Severe

– Frequent spontaneous bleeds into joints (hemarthrosis) and muscles

Hemophilia-Treatment

Fresh frozen plasma (FFP)– Contains II, V, VII, VIII, IX, X, XI, XIII

Problematic– Used pooled blood products, starting in 1970’s– Many/most developed hepatitis B and C– Later, HIVmany died

Now safer– Recombinant factors

Gene therapy?

Pseudo hemophilia-von Willebrand’s disease MC inherited hemophilia

– 1:1000 live births vWF helps to adhere platelets and carries Factor

VIII Affects platelets and factor VIII Prolongs BT by affecting aggregation Treatment: Cryoprecipitate (Plasma with extra

vWF and VIII) or vasopressin (DDAVP) IV or sc

Non Platelet disorders-Acquired

DIC (Consumptive) Liver disease Transfusion induced

Non Platelet. disorders-Acquired-II

Vitamin K deficiency– Malabsorption, Antibiotics

Circulating anticoagulant– Lupus, pregnancy, penicillin

Heparin Warfarin/Coumadin

Disseminated intravascular coagulation (DIC) A disease of excess clotting AND of bleeding Trigger is typically a massive event such as surgical

catastrophe or sepsis Begins thrombotic followed by consumptive and

fibrinolytic process– Prolonged PT and PTT, Thrombocytopenia– Decreased fibrinogen– Increased fibrin degradation products (Elevated D-

Dimer which is cross linked fibrin)

DIC-Treatment

Treat cause-Most important for survival FFP Platelets Red cells

Hypercoagulability

Hypercoagulability

Predisposition to clot formation (all of them to various degrees)– “Thromboembolic disease”

Deep vein thrombosis Pulmonary embolism

– Often missed, based on autopsy studies Suspect genetic cause in patients

– Young who develops 2+ clots– Family history (the importance of taking family history,

particularly if surgery planned!)

How do we prevent abnormal clotting? Maintaining homeostasis requires ability of

clotting to be balanced with breakdown of clots (fibrinolysis) and prevention of abnormal/inappropriate clotting– Protein C– Protein S– Anti-thrombin III

Absence of the above allows abnormal clotting Fibrinolytic system

Fibrinolytic system

Breaks down clot after formation Prevents abnormal clotting/Keeps system in

check Allows wound reparation and healing

Causes of hypercoagulability

Inherited disorders Dysfibrinogenemias/Fibrinolytic defects

Inherited prothrombotic disorders

Defects in coagulation inhibitors (5-15% of cases)– All are autosomal dominant traits– Anti-thrombin deficiency– Protein C deficiency– Protein S deficiency

Point mutations– Factor V Leiden (12-40% of cases)– Prothrombin gene mutation (6-10% of the cases)

Anti-thrombin deficiency

AT III blocks activity of activated factors normally, thus preventing abnormal clotting

If absent, risk of clotting higher Even heterozygotes have a 50% reduction

in activity (autosomal dominant inheritance)

Protein C deficiency

With Protein S blocks activity of activated factors

If absence, effect similar

Protein S deficiency

Similar

Point Mutations

Factor V Leiden Prothrombin gene mutation G20210A

Factor V Leiden

Amino acid substitution in Factor V gene– Prolongs the thrombogenic effect of Factor V activation– Results in activated protein C resistance

3% of population are heterozygotes Absent in Asians, African Americans, Native

Americans Heterozygocity increases clotting risk by 7 Fold Homozygocity increases risk of clotting by 20

Fold

Prothrombin gene mutation (G20210A) Point mutation G to A substitution on

prothrombin gene at position 2010 on the chromosome

Increases prothrombin level 30% Of those with family history of TE disease

18% are heterozygotes for this and of those with first DVT about 6%

Dysfibrinogenemias/Fibrinolytic disorders Sort of a waste basket of other assorted disorders

through different mechanisms CHF Metastatic cancer (Be sure to look for in

unexplained TE) Paroxysmal nocturnal hemoglobinuria (PNH) Essential thrombocytopenia Polycythemia rubra vera Dysfibrinogenemia (familial defect)

Dysfibrinogenemias/Fibrinolytic disorders-continued Circulating anti-coagulants (next slide)

– Anti-cardiolipin antibodies– includes Lupus anticoagulant (LA)

Behçet’s disease (vasculitis with oral and genital ulcers) Kawasaki’s (vasculitis with lymph node enlargement in

children which leads to coronary aneurysms Oral contraceptive pills Anti-estrogens (such as Tamoxifen) Homocysteinemia (next slide) DIC Nephrotic syndrome

Circulating anticoagulants Inhibit blood clotting by binding phospholipids May affect Factor VIII or IX May be seen in post-partum, HIV, and systemic lupus

erythematosis (SLE, Lupus) Typically prolong PT, PTT Bleeding can occur (though not always) especially if

thrombocytopenia or prothrombin deficiency PRESENCE OF LA PREDISPOSES PTS TO TE

DISEASE– Most pronounced when present in lupus– Less likely to cause DVT in pts that have isolated LA but not SLE.

Homocysteinemia

Elevated levels of this amino acid Often elevated levels in urine

(homocysteinuria) Can have Vitamin B12 deficiency May benefit from folic acid Associated with higher risk of heart disease

Hypercoagulability- Work up hints

First DVT/PE may or may not warrant work up– I.e.: Post op DVT– Long airplane ride

History of recurrent thrombus really mandates thorough evaluation (and likely lifelong treatment)

Always inquire about family history of blood clotting problems, warfarin use, etc.

If lupus anticoagulant (Anti-cardiolipin Ab)– PTT is usually gapped

Malignancies should always be in the back of

Hypercoagulability work-up specific tests CBC with platelet count PT PTT Factor V Leiden Prothrombin gene mutation Protein C Protein S Anti-thrombin III Homocysteine Anti-phospholipid antibodies (includes lupus anticoagulant) Other tests based on history

– DON’T MISS CANCER!!!!!!!!

Hypercoagulability-Treatment

First clot usually 3-6 months reasonable– Debated frequently in literature– A real inconvenience (Bleeding risk, lab testing)

Second clot usually lifelong anti-coagulation is warranted

Must weigh risks and benefits– Bleeding not uncommon on warfarin– Pregnancy contraindicates warfarin (teratogen)

Use LMWH

Case study

Testing– Ultrasound of leg

Lab tests? Family history? Treatment?

– Outpatient?– Inpatient?

How long?

Summary

Bleeding disorders are common and can be inherited or acquired

Drug effect on hemostasis remain the most common clinical entity

Venous thromboembolic disorders should prompt thorough work up to rule out hyper-coagulability

Where to get more information

Cecil’s or Harrison’s Any hematology text Bakerman’s ABC’s of Interpretive Lab

Data The Hemophilias NEJM Vol. 344, No. 23,

pgs 1773-9